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Guidelines for Clinical Care Quality Department Ambulatory

GERD Gastroesophageal Reflux (GERD) Guideline Team Team Leader Patient population: Adults Joel J Heidelbaugh, MD Objective: To implement a cost-effective and evidence-based strategy for the diagnosis and Family treatment of gastroesophageal reflux disease (GERD). Team Members Key Points: R Van Harrison, PhD  Diagnosis Learning Health Sciences Mark A McQuillan, MD History. If classic symptoms of and acid regurgitation dominate a patient’s history, then General Medicine they can help establish the diagnosis of GERD with sufficiently high specificity, although sensitivity Timothy T Nostrant, MD remains low compared to 24-hour pH monitoring. The presence of atypical symptoms (Table 1), although common, cannot sufficiently support the clinical diagnosis of GERD [B*]. Testing. No gold standard exists for the diagnosis of GERD [A*]. Although 24-hour pH monitoring

Initial Release is accepted as the standard with a sensitivity of 85% and specificity of 95%, false positives and false March 2002 negatives still exist [II B*]. lacks sensitivity in determining pathologic reflux but can Most Recent Major Update identify complications (eg, strictures, erosive , Barrett’s ) [I A]. Barium May 2012 has limited usefulness in the diagnosis of GERD and is not recommended [III B*]. Content Reviewed Therapeutic trial. An empiric trial of anti-secretory therapy can identify patients with GERD who March 2018 lack alarm or warning symptoms (Table 2) [I A*] and may be helpful in the evaluation of those with

atypical manifestations of GERD, specifically non-cardiac [II B*].  Treatment Ambulatory Clinical Lifestyle modifications. Lifestyle modifications (Table 3) should be recommended throughout the Guidelines Oversight treatment of GERD [II B], yet there is evidence-based data to support only and avoiding Karl T Rew, MD recumbency several hours after meals [II C*]. R Van Harrison, PhD Pharmacologic treatment. H2-receptor antagonists (H2RAs), proton pump inhibitors (PPIs), and prokinetics have proven efficacy in the treatment of GERD [I A*]. Prokinetics are as effective as H2RAs but are currently unavailable [III A*]. Carafate and are ineffective [III A*], but may Literature search service be used as supplemental acid-neutralizing agents for certain patients with GERD [II D*]. Taubman Health Sciences Library • Non-erosive reflux disease (NERD): Step-up (H2RA, then a PPI if no improvement) and step-down (PPI, then the lowest dose of acid suppression) therapy are equally effective for treatment

and maintenance [I B*]. On demand (patient-directed) therapy is the most cost-effective [I B]. For more information • Erosive esophagitis: Initial PPI therapy is the treatment of choice for acute and maintenance therapy 734-936-9771 for patients with documented erosive esophagitis [I A*]. www.uofmhealth.org/provide • Take PPIs 30-60 minutes prior to breakfast (and also dinner if taking twice daily) to optimize r/clinical-care-guidelines effectiveness [I B*]. Use generic and OTC formulations exclusively, eliminating need for prior authorizations. © Regents of the University of Michigan • Patients should not be left on anti-secretory therapy without re-evaluation of symptoms to minimize cost and the potential adverse events from [I B].

Surgery. Anti-reflux is an alternative modality in GERD treatment for patients with chronic These guidelines should not be reflux and recalcitrant symptoms [II A*], yet has a significant rate (10-20%). construed as including all Resumption of pre-operative treatment is common (> 50%) and may increase over time. proper methods of care or excluding other acceptable Other endoscopic treatments. While less invasive and with fewer complications, they have lower methods of care reasonably response rates than anti-reflux surgery [II C*], and have not been shown to reduce acid exposure. directed to obtaining the same results. The ultimate judgment  Follow up regarding any specific clinical procedure or treatment must be Symptoms unchanged. If symptoms remain unchanged in a patient with a prior normal endoscopy, made by the physician in light repeating endoscopy has no benefit and is not recommended [III C*]. of the circumstances presented by the patient. Warning signs. Patients with warning or alarm suggesting complications from GERD (Table 2) should be referred to a GERD specialist. Risk for complications. Further diagnostic testing (eg, EGD [esophagogastroduodenoscopy], 24- hour pH monitoring) should be considered in patients who do not respond to acid suppression therapy [I C*] and in patients with a chronic history of GERD who are at risk for complications. Chronic reflux has been suspected to play a major role in the development of Barrett’s esophagus, yet it is unknown if outcomes can be improved through surveillance and medical treatment [D*]. * Strength of recommendation: I = generally should be performed; II = may be reasonable to perform; III = generally should not be performed. Level of evidence supporting a diagnostic method or an intervention: A=randomized controlled trials; B=controlled trials, no randomization; C=observational trials; D=opinion of expert panel. 1

Figure 1. Diagnosis and Treatment of GERD

Table 1. Atypical Table 2. Alarm or Warning Table 3. Lifestyle Modifications Signs of GERD Signs Suggesting Complicated GERD Chronic Elevate head of bed 6-8 inches Asthma Decrease fatty meals Recurrent sore throat Stop Recurrent GI Avoid recumbency or sleeping for 3-4 hours after eating Dental enamel loss Iron deficiency Avoid certain foods: chocolate, , peppermint, caffeinated coffee and other beverages, onions, garlic, fatty foods, citrus, tomato Subglottic stenosis Weight loss Globus sensation Early satiety Avoid large meals Chest pain Weight loss Onset of symptoms at age > 50 Avoid medications that can potentiate symptoms: calcium channel blockers, beta-agonists, alpha- adrenergic agonists, , nitrates, and some sedatives (benzodiazepines).

2 UMHS GERD Guideline, September, 2013

Table 4. Medications for Acute Treatment and Maintenance Regimens

Drug Dose Equivalents a Dosage b OTC Generic c Brand c H2 receptor antagonists (Tagamet HB) 200 mg twice daily 200 mg twice daily $25 $25 NA cimetidine (Tagamet) 400 mg twice daily 400 mg twice daily $12 $25 NA (Pepcid) 20 mg twice daily 20 mg twice daily $11 $9 $655 (Axid) 150 mg twice daily 150 mg twice daily $43 $37 NA

Proton pump inhibitors (Dexilant) 30 mg daily 30 mg once daily NA NA $296 (Nexium) 20 mg daily 20 to 40 mg daily $25-34 $22-27 $271 (Prevacid) 30 mg daily 15 or 30 mg daily before breakfast $15-29 $15-24 $448 (Prilosec) 20 mg daily 20 or 40 mg daily before breakfast $15-30 $5-8 NA (Protonix) 40 mg daily 40 mg daily before breakfast NA $6 $465 (Aciphex) 20 mg daily 20 mg daily before breakfast NA $21 $567 a For each drug, the dose listed in this column has an effect similar to the doses listed in this column for other drugs. b Maximum GERD dose for PPIs except dexlansoprazole is the highest listed dose amount, but given twice daily before breakfast and before dinner. Dexlansoprazole maximum dose is 60 mg once daily. c Cost = For brand drugs, Average Wholesale Price minus 10%. AWP from Red Book Online 4/3/18. For generic drugs, Maximum Allowable Cost plus $3 from BCBS of Michigan MAC List, 4/1/18. Prices calculated for 30-day supply unless otherwise noted.

Clinical Background Clinical Problem endoscopic evidence of disease. Although these diagnostic limitations occur less often when patients present with the Incidence classic symptoms of heartburn and acid regurgitation, diagnosis may be difficult in patients with recalcitrant Gastroesophageal reflux disease (GERD) is a common courses and extraesophageal manifestations of this disease. chronic, relapsing condition that carries a risk of significant morbidity and potential mortality from resultant Diagnostic Problems complications. While many patients self-diagnose, self-treat and do not seek medical attention for their symptoms, others The lack of a gold standard in the diagnosis of GERD suffer from more severe disease with esophageal damage presents a clinical dilemma in treating patients with reflux ranging from erosive to ulcerative esophagitis. symptomatology. Many related syndromes including dyspepsia, atypical GERD, H. pylori-induced , More than 60 million adult Americans suffer from heartburn peptic disease and gastric may present similarly, at least once a month, and over 25 million experience making accurate history taking important. The most common heartburn daily. The National Ambulatory Medical Care referral to a gastroenterologist from primary care is for Survey (NAMCS) found that 38.53 million annual adult evaluation of refractory GERD. Even in these cases the pre- outpatient visits were related to GERD. For patients test sensitivity and specificity for accurate diagnosis remain presenting with GERD symptoms, 40-60% or more have low. Invasive testing is over-utilized and not always cost- reflux esophagitis. Up to 10% of these patients will have effective, given the relatively small risk of misdiagnosis erosive esophagitis on upper endoscopy. GERD is more based upon an accurate patient history. Empiric prevalent in pregnant women, and a higher complication rate pharmacotherapy is advantageous based on both cost and exists among the elderly. Patients with GERD generally convenience for the patient. report decreases in productivity, quality of life and overall well-being. Many patients rate their quality of life to be lower Treatment Decision Problems than that reported by patients with untreated angina pectoris or chronic heart failure. GERD is a risk factor for the Although empiric anti-secretory therapy with a histamine-2 development of esophageal , further receptor antagonist (H2RA) or a proton pump inhibitor (PPI) increasing the importance of its diagnosis and treatment. provides symptomatic relief from heartburn and regurgitation in most cases, the potential long-term adverse Extraesophageal manifestations associated with GERD effects of anti-reflux medications are unknown. No cases of occur in up to 50% of patients with non-cardiac chest pain, gastric cancer or carcinoid linked to use of the PPIs have 78% of patients with chronic hoarseness, and 82% of patients been reported since the advent of this class of medication with asthma. Over 50% of patients with GERD have no over 20 years ago. 3 UMHS GERD Guideline, September, 2013

stricture or adenocarcinoma of the esophagus are very rare Complications from GERD (eg, Barrett’s esophagus, unless the initial endoscopy shows esophagitis or Barrett’s adenocarcinoma of the esophagus) are rare but do exist; 10- esophagus. A normal endoscopy with symptomatic GERD 15% with GERD will develop Barrett’s esophagus, and 1- presents a good prognosis, and does not need to be repeated 10% of those with Barrett’s will develop adenocarcinoma for 10 years unless alarm or warning symptoms are present over 10-20 years. Chronic reflux has been suspected to play (Table 2). Long-term natural history studies are limited. a major role in the development of Barrett’s esophagus (specialized columnar epithelium or intestinal ), Diagnosis yet it is unknown if outcomes can be improved through surveillance and medical treatment. anti-secretory therapy Evidence-based limitations exist when trying to assess the has been shown to reduce the need for recurrent dilation from validity of the diagnostic modalities for GERD. Most studies formation. have flawed methods because no gold standard exists. However, the calculated numbers are helpful in providing a Previous cost-effectiveness models for endoscopic screening framework to assess available options. Recent studies were flawed in that certain studies examined only patients suggest that combining diagnostic modalities (omeprazole with erosive esophagitis and excluded patients with non- challenge test [daily omeprazole for two weeks], 24-hour pH erosive esophagitis (NERD), while some studies included monitoring, and endoscopy) may increase the sensitivity for data on anti-reflux surgery only for patients who failed diagnosis of GERD (approaching 100%), but this approach medical therapy. These studies also viewed a short-term is not practical in the routine clinical setting. analysis of therapeutic efficacy, rather than following patients over a lifetime, and did not allow for the switching 24-hour pH monitoring offers adequate sensitivity and from one particular medication to another. specificity in establishing a diagnosis of GERD in cases that do not readily respond to anti-secretory therapy. It can also help with patient compliance by establishing that acid Rationale for Recommendations production has been eliminated or reduced to zero. The UMHS approach to 24-hour pH monitoring includes: Etiology scheduling, availability, report turnaround time, patient satisfaction, cost, and insurance coverage. Most patients with GERD have normal baseline lower esophageal sphincter tone. The most common mechanism for History. Since GERD occurs with few if any abnormal acid reflux is transient relaxation of the lower esophageal physical findings, a well-taken history is essential in sphincter (≥ 90% of reflux episodes in normal subjects and establishing the diagnosis of GERD. Symptoms of classic 75% of episodes in patients with symptomatic GERD). Other burning in the chest, with sour or bitter taste, and acid mechanisms include breaching the lower esophageal regurgitation have been shown to correctly identify GERD sphincter because of increased intra-abdominal pressure with a sensitivity of 89% and specificity of 94%. Up to 1/3 (strain induced reflux) and a baseline low pressure at the of patients with GERD will not report the classic symptoms lower esophageal sphincter. The latter two mechanisms of heartburn and regurgitation. However, symptom increase in frequency with greater reflux severity. Other frequency, duration and severity are equally distributed factors include delayed gastric emptying (co-factor in 20% among patients with varying grades of esophagitis and of GERD patients), medication use (particularly calcium Barrett’s esophagus and cannot be used reliably to diagnose channel blockers), hiatal (increased strain induced complications of GERD. There may also be some symptom reflux and poor acid clearance from hernia sac), and poor overlap with other conditions (non-cardiac chest pain, cough, esophageal acid clearance (eg, esophageal dysmotility, etc.). scleroderma, decreased salivary production). PPI diagnostic test. A favorable symptomatic response to a short course of a PPI (once daily for two weeks) is considered Natural History to support a diagnosis of GERD when symptoms of non- cardiac chest pain are present. A meta-analysis found that a Most GERD patients (80-90%) do not seek medical attention successful short-term trial of PPI therapy did not confidently and will self-medicate with OTC anti-secretory therapy establish a diagnosis of GERD (sensitivity 78%, specificity (50%). In patients seeing physicians, most will have chronic 54%) when 24-hour pH monitoring was used as the reference symptoms that will occur off treatment. Patients with more standard. This may be due to an observed clinical benefit of severe esophagitis will have symptoms recur more quickly PPIs in treating other acid-related conditions (as seen in the and almost all will have recurrent symptoms and esophagitis heterogeneous dyspeptic population), patients with enhanced if followed up for ≥ 1 year. Progression of disease can be esophageal sensitivity to acid (without true GERD), or even seen in up to 25% of patients with esophagitis, but it is less due to a placebo effect. In those with non-cardiac chest pain, likely to occur if esophagitis is not present or is mild. (Using an empiric trial of high-dose omeprazole (40 mg AM, 20 mg the Los Angeles Classification for Gastroesophageal Reflux PM) had a sensitivity of 78% and specificity of 85%. Disease, this would be LA grade A or B.) Complications Standard dosages may have lower sensitivity and specificity. such as Barrett’s esophagus, esophageal ulcers, esophageal 4 UMHS GERD Guideline, September, 2013

Empiric or therapeutic trial. Diagnostic modalities cannot of complications (eg, Barrett’s esophagus, cancer) but reliably exclude GERD even if they are negative. Therefore, troublesome dysphagia and weight loss are predictive of an empiric trial of anti-secretory therapy may be the most complications. Endoscopy should be done for patients not expeditious way in which to diagnose GERD in those with responding to a twice-daily PPI. classic symptoms and who do not have symptoms suggestive of complications (eg, , stricture). (See discussion Endoscopic are indicated to detect Barrett’s of "step-up" therapy and "step-down" therapy in treatment esophagus and , but are not indicated section.) when the endoscopy is normal. Random biopsies and directed biopsies to nodular areas should be done if Barrett’s Empiric therapy should be tried for two weeks for patients esophagus is seen or eosinophilic esophagitis is suspected. with typical GERD symptoms. Treatment can be initiated with standard dosage of either an H2RA twice daily (on Routine endoscopy in the general population is not indicated. demand, taken when symptoms occur) or a PPI (30-60 High-risk patients for esophageal adenocarcinoma such as minutes prior to first meal of the day), with drug selection age ≥ 50, males, chronic GERD, , high body depending on clinical presentation and appropriate cost- mass index, central obesity, and tobacco use, may warrant effectiveness and the end point of complete symptom relief. endoscopy. (See Figure 1 and costs in Table 4). If symptom relief is not adequate and H2RA twice daily was initially used, then PPI Esophageal manometry. Esophageal manometry should be daily should be used. If PPI daily was initially used, then second line for diagnosis of GERD. Detection of achalasia, increase to maximum dose PPI daily or twice daily (30-60 spastic achalasia, or distal is critical if minutes prior to first and last meals). patient is having antireflux surgery. Adequate is another prerequisite for anti-reflux surgery. Esophageal For patients who initially present with more severe and more manometry is not indicated for the detection of GERD. High frequent symptoms of typical GERD, treatment may be resolution manometry is superior to standard manometry in initiated with higher and more frequent dosages of an H2RA the detection of major motility disorders mimicking GERD. or PPI. If symptom relief is not adequate from the initial dose (see Figure 1), then increase potency or frequency as needed Other Testing for GERD. Esophageal acid to obtain complete symptom relief: high-dose H2RA to PPI perfusion testing (also called Bernstein testing), esophageal daily, PPI daily or maximum dose PPI daily or twice daily. sensory testing, and barium esophagram are not indicated for If there is no response when using maximal doses and the diagnosis of GERD. Barium esophagram may be helpful frequencies, then diagnostic testing should be performed in the preoperative phase of anti-reflux surgery or in the after 8 weeks of therapy. evaluation of major motor disorders (eg, achalasia, ) after a normal endoscopy. If the patient responds with symptom relief, give 8-12 weeks of therapy, ie, enough to heal undiagnosed esophagitis. If the Treatment patient has complete symptom relief at 8-12 weeks, taper over 1 month to lowest effective dose of the medication that Lifestyle modifications. For patients with a history typical gives complete relief, eg, H2RA on demand, PPI every other for uncomplicated GERD, expert opinion is to discuss and day. If symptoms recur, put patient back on the lowest offer various lifestyle modifications throughout the course of effective medication and dose, and consider further testing GERD therapy (see Table 3). Neither the efficacy nor the depending on clinical presentation and course. potential negative effects of lifestyle changes on a patient’s quality of life have been adequately examined. With Patients who present with atypical or extraesophageal relatively little data available, it is reasonable to educate manifestations take a longer time to respond to empiric patients about factors that may precipitate reflux. Only therapy, and often require twice-daily dosing. If there is no recently has there been evidence to support weight loss and improvement at all in symptoms after two months, further avoiding recumbency in favorable outcomes. testing should be pursued. Head elevation. Numerous studies have indicated that Endoscopy and in GERD. Endoscopy is used to elevating the head of a patient’s bed by 4 to 8 inches, as well detect mucosal injury, esophageal stricture, Barrett’s as avoiding recumbency for 3 hours or greater after a large esophagus or . Eosinophilic esophagitis, or fatty meal, may decrease distal esophageal acid exposure. diagnosed by mucosal changes and biopsies (at least 5 in However, data reflecting the true efficacy of this maneuver proximal and distal esophagus), is increasingly important. in patient reported outcomes is lacking. It has also been Mucosal injury is seen in less than 50% of patients with suggested that patients should avoid sleeping on additional GERD symptoms, and therefore the diagnostic sensitivity is pillows, as this may increase abdominal pressure and lead to less than 50%, but specificity is 95%. increased reflux.

Esophagitis is best defined by the Los Angeles Classification Avoid certain foods. Several foods are believed to be of Gastroesophageal Reflux Disease (LA grades A through direct esophageal irritants: citrus juices, carbonated D). Alarm signs and severity of symptoms are not predictive beverages, coffee and , chocolate, spicy foods, fatty 5 UMHS GERD Guideline, September, 2013 foods, or late evening meals. However, no randomized these OTC H2RAs. The OTC H2RAs are believed to be controlled trials are available to support recommendations to superior in efficacy when compared to antacids, alginic acid, avoid or minimize these foods. Individualized dietary and placebo. modification trials may be reasonable to help elucidate potential causative dietary factors. Numerous randomized controlled trials have demonstrated that standard dose H2RAs are more effective than placebo at Weight loss. A direct association among weight, reflux, relieving heartburn in cases of GERD, with symptomatic and reflux complications has been demonstrated. Weight loss relief reported in 60% of cases. A systematic review found has been shown to improve global symptom scores, that people in trials on H2RAs had faster healing rates than particularly if weight gain occurred before the onset of people in trials on placebo: over a 4-8 week period a healed GERD symptoms. esophagitis rate of 50% on H2RA and 24% on placebo.

Smoking cessation and alcohol minimization. Smoking Both higher doses and more frequent dosing of H2RAs cessation and the elimination or minimization of alcohol are appear to be more effective in the treatment of reflux also encouraged for a variety of health reasons. Both nicotine symptoms and healing of esophagitis. If the patient is on and alcohol have been shown to decrease lower esophageal maximal therapy, the disadvantages include cost and sphincter pressure and lead to further esophageal irritation. compliance. Some patients will develop tolerance to the A systematic review found that smoking was associated with H2RAs, with decreased efficacy observed after 30 days of an increase in GERD symptoms (over 1-2 days); yet smoking treatment. cessation was not shown to decrease GERD symptoms in 3 low-quality studies. Alcohol use may or may not be Most evidence describing adverse effects is from case reports associated with reflux symptoms. or uncontrolled trials. H2RAs have been associated with rare cytopenias, gynecomastia, function test abnormalities, Avoid medications that decrease lower esophageal and hypersensitivity reactions. In the long-term, there have pressure or irritate the esophagus. Medications that decrease been no controlled trials with follow-up on the safety of lower esophageal sphincter pressure should be avoided in chronic use of H2RAs. Cimetidine may cause gynecomastia patients with symptoms of GERD. These medications or antiandrogenic side effects, and may interact with include calcium channel blockers, beta-agonists, alpha- medications metabolized by cytochrome P450. adrenergic agonists, theophylline, nitrates, PDE-5 inhibitors (eg, avanafil, , , ), Proton Pump Inhibitors (PPIs). Several studies have anticholinergics, narcotics, and some sedatives demonstrated that on-demand therapy with PPIs is the most (benzodiazepines). Medications that irritate the esophagus cost-effective method for non-erosive reflux disease include NSAIDS, ferrous sulfate, and . (NERD). Evidence from numerous randomized controlled trials has shown that PPIs are more effective than both Avoid tight clothing around waist. Another anecdotal H2RAs and placebo in controlling symptoms from erosive suggestion is that patients refrain from wearing tight clothing reflux disease (83% compared to 60% and 27%, around the waist to minimize strain-induced reflux. respectively) over a 4-8 week period. One systematic review compared the efficacy of PPIs and H2RAs and found that a Over-the-counter (OTC) remedies. Antacids and OTC greater number of people improved symptomatically with anti-secretory therapy (H2RAs, PPIs) are appropriate initial PPIs, yet the difference was not significant for heartburn patient-directed therapy for GERD. Antacids (Tums, remission. One randomized controlled trial showed that at 12 Rolaids, Maalox) and combined with alginic acid months, significantly more people were still in remission (Gaviscon) have been shown to be more effective than with omeprazole compared to . Another placebo in the relief of daytime GERD symptoms. Two long- randomized controlled trial found that treatment with term studies suggest that approximately 20% of patients omeprazole was more likely than ranitidine to improve experience some relief from over-the-counter agents. symptom and psychological well-being scores. [Note: ranitidine was removed from the US market by the FDA in H2 receptor antagonists (H2RAs). The histamine type-2 April 2020 as part of an investigation of a contaminant receptor antagonists (H2RAs: cimetidine, famotidine, and known as N-Nitrosodimethylamine (NDMA) in ranitidine nizatidine) have been approved for use in the US as OTC products.] preparations at a dose that is uniformly one-half of the standard lowest prescription dosage for each compound. At In the treatment of erosive esophagitis, PPIs had faster these dosages, the H2RAs decrease gastric acid production, healing rates than either H2RAs or placebo (78% compared particularly after eating a meal, without affecting to 50% and 24%, respectively) over a 4-8 week period. No esophagogastric barrier dysfunction. The H2RAs are randomized controlled trials have examined therapy for a virtually interchangeable at these dosages, with similarities longer period of time. in the rapidity and duration of action. The OTC costs are equivalent (although the generic costs differ by dosage). One randomized controlled trial found no evidence of a Some patients may predict when they will suffer reflux significant difference among four PPIs, including symptomatology and may benefit from premedication with lansoprazole, omeprazole, pantoprazole, and rabeprazole in 6 UMHS GERD Guideline, September, 2013 the healing of erosive esophagitis. Efficacy in pH changes this modality to be more effective than doubling the dose of was not studied. The least expensive PPIs are omeprazole a PPI in patients with non-erosive disease. and lansoprazole, which are available generically and OTC. A single study showed that esomeprazole, the S-isomer of Surgical treatment. Anti-reflux surgery is an accepted omeprazole, at doses of 20 mg and 40 mg is more effective alternative treatment for symptomatic reflux of acid or bile than omeprazole 20 mg in both healing and symptom in certain patients. The basic tenets of surgery are reduction resolution in GERD patients with reflux esophagitis, with a of the hiatal hernia, repair of the diaphragmatic hiatus, tolerability profile comparable to that of omeprazole. A strengthening the attachment between the gastroesophageal randomized controlled trial compared esomeprazole 40 mg junction and the posterior diaphragm, and strengthening the to lansoprazole 30 mg. Esomeprazole was superior in healing anti-reflux barrier by adding a gastric wrap around the and symptom control, with superiority highest in more gastroesophageal junction (fundoplication). Controlled trials severe degrees of esophagitis. comparing open and laparoscopic approaches have shown similar efficacy and complications, with lower morbidity and The potential benefit of chronic PPI therapy in patients with shorter hospital stays in the laparoscopic repair group. chronic or complicated GERD generally outweighs any theoretical risk of adverse events. Risks associated with Post-surgical complications are common, but they are chronic PPI therapy include Clostridium-difficile-associated typically short term and manageable in most instances. (adjusted odds ratio [AOR] = 2.1 – 2.6); Short-term solid food dysphagia occurs in 10% of patients community-acquired pneumonia (AOR = 1.5 – 1.9); (2-3% have permanent symptoms) and gas occurs in fracture (AOR = 1.4 – 1.6); deficiency (AOR = 7-10% of patients. Diarrhea, , and early satiety occur 1.0 – 4.46); antiplatelet interactions (AOR = 1.25). Data more rarely. While some complication occurs in up to 20% regarding risks of bone fracture and antiplatelet interactions of patients, major complications occur in only 3-4% of are controversial. A 2011 FDA warning recommends patients. Patient satisfaction is high when GERD symptoms periodic surveillance of serum magnesium levels due to are well controlled. potential hypomagnesemia. Controlled trials comparing anti-reflux surgery to antacids, Since all data were collected retrospectively, a definitive H2RAs and PPIs have shown marginal superiority to cause-and-effect relationship cannot be proven. All patients surgery. Studies comparing surgery with proton pump on long-term PPI therapy should be re-evaluated periodically inhibitors have shown similar efficacy if PPI could be titrated to determine need and to weigh potential risks versus to response. Long-term follow-up trials have shown that 52% benefits of therapy. of patients are back on anti-reflux medications 3-5 years after surgery, most likely secondary to a combination of poor Baclofen patient selection and surgical breakdown.

While not considered to be first-line therapy, baclofen has The choice to consider anti-reflux surgery must be been shown to offer symptomatic relief for patients with individualized. Patients should have documented acid reflux, GERD. This approach is aimed at decreasing the number of a defective anti-reflux barrier in the absence of poor gastric transient lower esophageal sphincter relaxations and emptying, normal esophagus motility and at least a partial increasing lower esophageal sphincter tone. These effects response to acid reduction therapy. Surgery appears to be have been observed most significantly after eating a meal. most effective for heartburn and regurgitation (75-90%) and less effective for extraesophageal symptoms (50-75%). Prokinetics Other endoscopic treatments for GERD. Radiofrequency Previous prokinetic medications (eg, cisapride) were taken heating of the GE junction (Stretta), endoscopic gastroplasty off the US market several years ago due to increased (Bard, Wilson Cook), injections and full thickness cardiovascular risks. , a newer generation gastroplication have been shown to improve quality of life in prokinetic not currently available in the US, has been shown sham controlled trials. Duration of effect and acid control are to improve reflux symptoms and gastric emptying when less than surgical fundoplication (30-50% compared to > combined with omeprazole. 70% at three years). Most of the commercial products for endoscopic anti-reflux treatments have been removed from Alternative Therapies the market mainly for non-coverage by insurance companies.

No randomized controlled trials have been conducted to date Treatment Failure to compare treatment outcomes between conventional anti- secretory therapy and alternative therapies. Use of Empiric treatment should be limited; if no response is seen demulcents (eg, licorice root, marshmallow), ginseng, and after 8 weeks of anti-secretory therapy, consider referring the apple cider vinegar have shown varying degrees of patient for upper endoscopy. Treatment response should be symptomatic improvement in small numbers of patients. present in 2-4 weeks for patients with typical symptoms. Acupuncture may also have some benefit, as one trial found Patients with atypical symptoms also have an initial response in one month, but may require 3-6 months for maximal 7 UMHS GERD Guideline, September, 2013 response. Patients with atypical symptoms may require source of symptoms. H2RAs should not be administered at higher PPI doses for response. the same time as PPIs and should be taken at bedtime.

Empiric treatment in patients with atypical symptoms is Step-down therapy. Once symptoms are controlled after appropriate if typical symptoms are also present. 24-hour step-up therapy, step-down therapy commences with the esophageal pH monitoring off of anti-reflux medications patient taking a PPI for 8 weeks, followed by an H2RA if might be the best diagnostic approach initially in patients GERD symptoms were adequately controlled with a PPI, with atypical symptoms only since ≤ 30% of patients will then stepping down further to on-demand use of antacids if have GERD associated symptoms. If patients with atypical the patient was while taking an H2RA. The symptoms do not respond to treatment in 1-3 months, then majority of patients who take more than a single daily dose GERD is not likely the cause and the other diagnoses should of a PPI and who experience relief of symptoms can be be entertained. successfully stepped down to single-dose therapy without a recurrence of reflux symptoms. However, a small percentage Maintenance Regimens of patients with refractory GERD will need long-term therapy with higher doses of a PPI to control symptoms. The goal of maintenance anti-secretory therapy is to have a symptom-free individual without esophagitis. Multiple On demand therapy. Treatment can be initiated with regimens are used to accomplish this. Increasing severity of standard dosage of either a PPI daily or an H2RA twice daily esophagitis is associated with increasing need for potent acid on demand (patient directed therapy). Drug selection reduction (ie, PPI long-term maintenance). Physicians depends on clinical presentation, cost-effectiveness, and end should ask if symptoms have resolved or are persisting. point of appropriate symptom relief. When needed, an appropriate workup should be instituted (Figure 1). Do not continue anti-secretory therapy indefinitely without re-evaluating symptoms. Regular re- Special Circumstances evaluation can help avoid adverse events and minimize costs. Older Adults

Since most individuals with GERD do not undergo In patients over the age of 50, new onset GERD is an alarm endoscopy, chronic acid suppression is tailored to the sign; endoscopy should be the initial diagnostic examination. individual. Options include: step-up therapy (starting less If reflux is still considered the major cause after negative potent agents and moving up for treatment response), step- endoscopy, empiric therapy would then be appropriate. down therapy (using potent acid suppression initially then decreasing the dose or moving to less potent agents to tailor Pregnancy to the individual’s response), on demand (patient-directed) therapy, or surgery. All options have the goal of complete New onset GERD symptoms are common during pregnancy symptom relief. due mainly to the mechanical pressure placed on the and intestinal tract as the uterus enlarges. Therapy for GERD Step-up therapy. If a patient does not respond to an H2RA during pregnancy usually takes a step-wise approach, within two weeks, the patient should be switched to a PPI, starting with lifestyle modifications often combined with a again emphasizing it be used 30 minutes to 1 hour prior to trial of calcium containing antacids. If this does not meals so that the PPI has time to interact with an activated sufficiently treat the symptoms, H2RAs (eg, cimetidine, pump. famotidine, and nizatidine) are considered safe in pregnancy and can be taken to alleviate symptoms. If symptoms persist If the patient does not respond to this program, double-dose despite these efforts, PPIs can be considered (caution advised PPI therapy (twice daily; 30 minutes before breakfast and 30 during pregnancy; possible risk of teratogenicity based on minutes before dinner) may be effective in reducing conflicting human data). symptoms. If the patient does not respond to this program, the patient likely does not have reflux as a source of their Atypical Manifestations of GERD symptoms, and diagnostic testing is appropriate.

As noted in Table 1, GERD may manifest atypically as Approximately 40% of patients requiring PPI therapy will pulmonary (asthma, chronic cough), laryngeal (laryngitis, need increasing dosage over time. Tolerance to H2RAs hoarseness, sore throat, globus, throat clearing), or cardiac occurs over time. The main goal is to use the lowest dose and (chest pain) symptoms, often without symptoms of heartburn least potent medication to obtain a complete and sustained and regurgitation. Mechanisms include direct contact and symptomatic response. microaspiration of small amounts of noxious gastric contents

into the larynx and upper bronchial tree triggering local Breakthrough symptoms are common and can be treated with irritation, and cough, and acid stimulation of vagal afferent antacids and/or nocturnal H2RAs. This approach should be neurons in the distal esophagus causing non-cardiac chest limited to those few individuals who are not getting pain and vagally-mediated bronchospasm or asthma. symptomatic response, yet have defined reflux as their 8 UMHS GERD Guideline, September, 2013

Laryngeal neuropathy has been implicated as a cause for A systematic review on chronic cough found there is laryngitis symptoms and cough. insufficient evidence to definitely conclude that PPI treatment is beneficial for cough associated with GERD in Pulmonary symptoms. Asthma and GERD are common adults, although a small beneficial effect was seen in conditions that often coexist, with 50-80% of asthmatics subgroup analysis. having GERD and up to 75% having abnormal pH testing. However, only 30% of patients who have both GERD and asthma will have GERD as the cause for their asthma. The Controversial Areas causal relationship between asthma and GERD is difficult to establish because either condition can induce the other. Barrett’s Esophagus Screening and Treatment GERD can cause asthma as noted above, and asthma can cause increased reflux by creating negative intrathoracic Barrett’s esophagus is present when intestinal epithelium pressure and overcoming the lower esophageal sphincter () replaces normal squamous epithelium barrier. Furthermore, medications used for asthma, such as in the tubular esophagus. Barrett’s esophagus carries a small bronchodilators, are associated with increased reflux risk of progressing to esophageal adenocarcinoma. Most symptoms. Historical clues to GERD-related asthma may patients who develop esophageal adenocarcinoma are include asthma symptoms that worsen with big meals, believed to progress from Barrett’s epithelium to low-grade alcohol, or a supine position, or adult-onset and medically , then to high-grade dysplasia, and then to cancer. refractory asthma. Diagnostic testing with pH probe and The overall progression of non-dysplastic Barrett’s EGD have limited utility in establishing causality in this epithelium to cancer is about 0.2% per year. Symptoms do population. not predict risk for cancer. Risk factors for progression include long-segment Barrett’s esophagus, male sex, tobacco Laryngeal symptoms. In patients presenting with laryngeal use, and likely abdominal obesity. Most patients with low- symptoms, about 10% of hoarseness, up to 60% of chronic grade dysplasia will revert to non-dysplastic epithelium or laryngitis and refractory sore throat, and 25-50% of globus remain low grade (60-80%); the progression of high-grade sensation may be due to reflux. EGD and pH testing are dysplasia to cancer is 6% per year. frequently normal in this population. Reflux laryngitis is usually diagnosed based on laryngoscopic findings of Endoscopic surveillance of Barrett’s esophagus is considered laryngeal erythema and edema, posterior pharyngeal standard, but intervals are very controversial. Since coblestoning, contact ulcers, granulomas, and interarytenoid progression is variable, the overall incidence of cancer is low changes. However, a study found these signs to be (6,000-7,000 new cases per year), and surveillance of nonspecific for GERD, noting at least 1 sign in 91 of 105 Barrett’s esophagus at intervals of less than 5 years is cost- (87%) healthy people who did not have reflux or laryngeal prohibitive (≥ $100,000 per quality adjusted life-year). The complaints. Many of these signs may be due to other diagnosis of all types of dysplasia is subject to error laryngeal irritants such as alcohol, smoking, postnasal drip, and intra- and inter-observer bias. Most overcalling occurs viral illness, voice overuse, or environmental allergens, between non-dysplastic and low-grade dysplasia and low- suggesting their use may contribute to over-diagnosis of grade to high-grade dysplasia. Dysplasia should be GERD. This also may explain why many patients (up to 40- confirmed by two experienced pathologists before surgery or 50%) with laryngeal signs don’t respond to aggressive acid endoscopic treatment is attempted. therapy. Posterior laryngitis, medial erythema of false or true vocal cords and contact changes (ulcers and granulomas) are Current accepted monitoring intervals are 3-5 years for no more common in GERD patients and predict a better dysplasia, 6-12 months for low-grade dysplasia, and 3 response to acid reduction. months for high-grade dysplasia. Endoscopic biopsies should be done in a standard manner based on past . Treatment. Aggressive acid reduction using PPIs twice Biopsies from nodular areas should be examined separately. daily before meals for at least 2-3 months is now considered Endoscopy for Barrett’s detection or monitoring should be the standard treatment for atypical GERD and may be the done only after adequate GERD control for 3 months. best way to demonstrate a causal relationship between GERD and extraesophageal symptoms. Double blind, Prevention of cancer in Barrett’s esophagus is also placebo controlled trials have not shown significant benefit controversial. Proton pump inhibitors should be given to for PPI twice daily treatment for laryngeal symptoms. control GERD symptoms. Single dose and more intensive Similar trials in asthma have shown marginal benefits in treatment to eliminate esophageal acid exposure have not FEV1 rates only when nocturnal GERD symptoms are also been proven to reduce cancer risk. Low-dose reduces present. Both groups of studies demonstrate the need for cancer risk, but should be reserved for Barrett’s esophagus better parameters for patient selection. Anti-reflux surgery patients who have cardiovascular risk factors for which aimed at controlling asthma through prevention of GERD aspirin is indicated. has a lower rate of success than anti-reflux surgery aimed at treating heartburn (45-50% vs. 80-90% respectively). Endoscopic and surgical therapies for Barrett’s esophagus are evolving. The use of radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR) should be reserved for 9 UMHS GERD Guideline, September, 2013 high-grade dysplasia confirmed by two pathologists. If literature searches were initially reviewed and accepted as treatment of non-dysplastic or low-grade dysplasia is being adequate through the time they were performed: considered, the use of RFA or EMR should be a shared American Gastroenterological Association: Position decision-making between the treating physician and the statement on the management of gastroesophageal reflux patient. Data to date show that reversion to squamous disease, 2008, literature search through early 2007. epithelium can persist for up to 5 years after endoscopic American Society for Gastrointestinal Endoscopy: Role ablation. of endoscopy in the management of GERD, 2007,

literature search through March 2008. Esophagectomy is the treatment of choice for esophageal adenocarcinoma. Most patients with high-grade dysplasia Society of American Gastrointestinal and Endoscopic can be treated with endoscopic eradication (70-80%). Less Surgeons: Guidelines for surgical treatment of morbidity is found with endoscopic ablation than gastroesophageal reflux disease, 2010, literature search esophagectomy with gastric pull-up. EMR is valuable to through early 2006. determine the existence of cancer with visible mucosal A search of more recent literature was conducted irregularities in dysplastic epithelium, and may effectively prospectively on Medline from January 2007 (end of AGA treat intramucosal . search) through March 2011, except January 2006 was the start date for endoscopy (since ASGE search) and January Before esophagectomy, patients with high-grade dysplasia or 2008 was the start date for surgical treatment (since SAGES intramucosal carcinoma should be referred to surgical search). The major keywords were: gastroesophageal reflux centers specializing in the treatment of foregut cancers and disease (or GERD, NERD [non-erosive reflux disease], high-grade dysplasia. NEED [non-erosive ]), human adults, English language, guidelines, clinical trials, and cohort studies. Terms used for specific topic searches within the Treatment for H. pylori major key words included: symptoms and classification (atypical symptoms, heartburn, retrosternal burning Patients with predominant GERD symptoms have a similar sensation precipitated by meals or a recumbent position, or lower frequency of H. pylori positivity than the general hoarseness, laryngitis, sore throat, chronic cough, chest population. Successful treatment of H. pylori has not been pain, bronchospasm/asthma, dental erosions), , shown to reduce predominant GERD symptoms. Some lymphocytic esophagitis, non acid reflux and weekly acid studies have shown decreased PPI effectiveness after reflux, nocturnal (or nocturnal breakthrough, night time), successful H. pylori treatment, but this is still controversial. endoscopy, pH recording, manometry, provocative testing One randomized controlled trial demonstrated that H. pylori (Bernstein’s), video esophagography, empiric/therapeutic eradication leads to more resilient GERD. Treatment of H. trial to acid suppression, lifestyle measures/treatment pylori is not indicated for patients with GERD. (avoiding fatty foods, chocolate, peppermints, - containing beverages; recumbency for 3 hours after a meal; elevating head of bed; weight loss), antacids, alginic acid Related National Guidelines (gaviscon), carafate, prokinetic agents (cisapride, , bethanechol, dromperidone), H2 receptor This guideline is consistent with: antagonists (nizatidine, ranitidine, famotidine, cimetidine), proton pump inhibitors (omeprazole, lansoprazole, American College of Gastroenterology: Updated guidelines rabeprazole, pantoprazole, esomeprazole) – toxicity and for the diagnosis and treatment of Gastroesophageal adverse reactions/events, proton pump inhibitors – other Reflux Disease, 2005 references, baclofen, fundoplication (open vs. laparoscopy; American Gastroenterological Association: Position endoscopic antireflux procedures), Barrett's esophagus statement on the management of gastroesophageal (screening, surveillance). Detailed search terms and strategy reflux disease, 2008 available upon request. American Society for Gastrointestinal Endoscopy: Role of endoscopy in the management of GERD, 2007 The search was conducted in components each keyed to a Society of American Gastrointestinal and Endoscopic specific causal link in a formal problem structure (available Surgeons: Guidelines for surgical treatment of upon request). The search was supplemented with very gastroesophageal reflux disease, 2010 recent information available to expert members of the panel, including abstracts from recent meetings and results of (See annotated references.) clinical trials. Negative trials were specifically sought. The search was a single cycle.

Strategy for Literature Search Conclusions were based on prospective randomized controlled trials if available, to the exclusion of other data; if The literature search began with the results of the literature randomized controlled trials were not available, searches performed through May 2006 for the previous observational studies were admitted to consideration. If no versions of this guideline. The results of three more recent 10 UMHS GERD Guideline, September, 2013 such data were available for a given link in the problem A consensus statement outlining recommendations in the formulation, expert opinion was used to estimate effect size. diagnosis and treatment of GERD.

American Gastroenterological Association: Kahrilas PJ, Disclosures Shaheen NJ, Vaezi MF, Hiltz SW, Black E, Modlin IM, Johnson SP, Allen J, Brill JV. American Gastroenterological The University of Michigan Health System endorses the Association Medical Position statement on the management Guidelines of the Association of American Medical Colleges of gastroesophageal reflux disease. Gastroenterology 2008 and the Standards of the Accreditation Council for Oct; 135(4):1383-91, 1391.e1-5. Continuing Medical Education that the individuals who A consensus statement outlining recommendations for the present educational activities disclose significant diagnosis and treatment of GERD. relationships with commercial companies whose products or services are discussed. Disclosure of a relationship is not Standards of Practice Committee, Am Soc for intended to suggest bias in the information presented, but is Gastrointestinal Endoscopy, Lichenstein ER, Cash BD et al. made to provide readers with information that might be of Role of endoscopy in the management of GERD Aug 2007. potential importance to their evaluation of the information. Gastrointestinal Endoscopy, 2007; 66(2):219-24.

A consensus statement of recommendations concerning Team Member Relationship Company endoscopy in managing GERD. Joel J Heidelbaugh, MD None Mark A McQuillan, MD Speakers Takeda, Pfizer, Heidelbaugh JJ, Goldberg KL, Inadomi JM. Adverse risks Bureau Astra Zeneca associated with proton pump inhibitors: a systematic review. R Van Harrison, PhD None Gastroenterology and 2009;5(10):725-34. Timothy T Nostrant, MD None A systematic review of the literature which examines potential risks of PPI therapy.

Review and Endorsement Heidelbaugh JJ, Nostrant TT. A Cost-Effective Approach to the Pharmacologic Management of Gastroesophageal Reflux Disease. Drug Benefit Trends 2004;16:463-471. Drafts of this guideline were reviewed in clinical conferences and by distribution for comment within departments and An in-depth examination of various cost-effective divisions of the University of Michigan Medical School to approaches to GERD treatment. which the content is most relevant: Family Medicine, General Medicine, and Gastroenterology. The Executive Heidelbaugh JJ, Nostrant TT. Medical and surgical Committee for Clinical Affairs of the University of Michigan management of gastroesophageal reflux disease. In: Hospitals and Health Centers endorsed the final version. Heidelbaugh JJ (ed). Clinics in Family Practice: Gastroenterology. Philadelphia, PA: Elsevier, September 2004, 6(3):547-568. Acknowledgements A systematic review of the literature and evidence-based recommendations for practice in the diagnosis and The following individuals are acknowledged for their treatment of GERD. contributions to previous versions of this guideline. Kahrilas, PJ. Gastroesophageal Reflux Disease. JAMA. 2002: Clara Kim, MD, General Medicine; R. Van Harrison, 1996;276(12):983-988. PhD, Medical Education; Joel Heidelbaugh, MD, Family A comprehensive review of treatment of GERD with less Medicine; Timothy Nostrant, MD, Gastroenterology. emphasis on diagnostic modalities.

2006: Joel J Heidelbaugh, MD, Family Medicine; Arvin S Numans Me, Lau J, deWit NJ, Bonis PA. Short-term Gill, MD, Internal Medicine; R. Van Harrison, PhD, treatment with proton-pump inhibitors as a test for Medical Education; Timothy T Nostrant, MD, gastroesophageal reflux disease: a meta-analysis of Gastroenterology. diagnostic test characteristics. Annals of Internal Medicine, 2004; 140(7):518-27. A systematic review of this literature, with 15 studies Annotated References showing the limited sensitivity and specificity of successful short-term treatment with PPI in establishing American College of Gastroenterology: DeVault KR, Castell the diagnosis when GERD is defined by 24-hour pH DO. Updated Guidelines for the Diagnosis and Treatment of monitoring. Gastroesophageal Reflux Disease. American Journal of Gastroenterology, 2005; 100:190-200. 11 UMHS GERD Guideline, September, 2013

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Guidelines for surgical treatment of gastroesophageal reflux disease. Los Angeles (CA): Society of American Gastrointestinal and Endoscopic Surgeons (SAGES); 2010 Feb. A consensus statement of current recommendations for surgical treatment of GERD.

Sridhar, S. Clinical economics review: cost-effectiveness of treatment alternatives for gastro-oesophageal reflux disease. Alim Pharmacol Ther 1996;10:865-873. An economic appraisal reviewing different treatment modalities and their cost-effectiveness. Proton pump inhibitors are considered more cost effective than H2 receptor antagonists in those with documented erosive esophagitis.

Vaezi, M. Gastroesophageal reflux disease and the larynx. J Clin Gastroenterol, 2003; 36(3):198-203. Presents the rational for an approach to identifying patients whose laryngeal signs and symptoms are due to GERD.

12 UMHS GERD Guideline, September, 2013